**3. Conclusions**

DM is a growing global pandemic. DM is associated with several severe complications which have a major impact on patient outcomes and quality of life, and which make up a considerable component of healthcare budgets worldwide. Diabetic complications include cardiovascular disease, retinopathy, nephropathy, neuropathy (including diabetic foot syndrome) and osteopathy. Gender has been proposed across numerous studies as an important variable in the risk of development of these complications. However, teasing apart the role of gender is complex. Both the physiological impact of sex and the psychosocial impact of gender on behaviour and treatment are confounded by numerous factors. These include direct and indirect biological traits that associate with each gender, from hormone levels (which are

vastly different for women post-menopause) to average height, life span and access to appropriate treatment. Many of these biological traits, and also psychosocial and socioeconomic traits that impact risk vary widely geographically. Understanding the epidemiology and physiological mechanisms of DM-associated complications, including the role of gender, allows for the implementation of appropriate treatment and research programmes that ultimately reduce morbidity and mortality.

In the non-DM population, oestrogens such as estradiol are protective against some of these comorbidities but the protective effects are often diminished in a DM context. This pattern is evident in both CVD and CKD where women with DM undergo a much larger relative increase in risk compared to men. Numerous studies have also shown that women are less often prescribed ACE inhibitors and lipid lowering drugs, including statins [56–60]. This prescription bias compounds the higher rates of CVD and CKD in women with T2DM, leading to increased mortality rates, a major factor in the high T2DM-assocaited mortality in women [30]. Therefore, particular awareness needs to be paid to the gender discrepancy in patient care in the context of T2DM in order to address this inequality and improve outcomes for women living with T2DM.

The onset of diabetic retinopathy is also linked to sex hormones - with levels of androgens correlating to likelihood of diagnosis. There is therefore increased incidence of diabetic retinopathy in men compared to women. Contrasting to this, neuropathy incidence, though higher in men, does not correlate directly with gender but instead with height which is a predictor of neuropathy development in both diabetic and non-diabetic populations [111, 118]. Therefore the higher rates in men in many regions are likely due to the greater average height of men with the causality possibly being longer nerve fibres which are more susceptible to injury and take longer to heal [111, 118].

Diabetic osteopathy is one of the less-reported complications of DM. People living with T2DM experience higher fracture rates both due to increased rates of falling and due to poorer bone health, which is present despite increased BMD [159]. In terms of the role of gender in diabetic osteopathy, the disorder follows an opposite pattern to that seen in CVD and DKD. Poor bone health experienced primarily by women in the non-DM population as they age is largely absent in men, but in the context of DM there is an increased relative risk for men to experience, for example, hip fracture [149, 156]. Fractures such as these are associated with high morbidity, especially functional limitations that results in loss of independence – physically and economically [178].

Interestingly, the overall mortality rates and cost of treatment associated with DM are higher in women than in men despite the general preponderance of comorbidity in men. A number of factors may explain this discrepancy. Firstly, women with DM are older, and epidemiologically there is increased cost of treatment and higher mortality with age. Secondly, regions with high DM-associated mortality (low- and middle-income countries) also report higher rates of DM in women [1]. Finally, men are reported to develop DM with a reduced risk-factor burden (eg. lower BMI). Though this indicates a greater risk of DM development for men, it also signifies that women, once they do develop DM, are diagnosed with such along with a greater set of risk factors for DM complications. These risk factors include inadequate blood glucose control, high blood pressure, high BMI and reportedly less frequent exercise [179]. Though not all women will experience pregnancy, for those that do, their glycaemic control during this time is a strong predictor of future development of T2DM [180]. Targeting those women who experience gestational diabetes for education or treatment options for T2DM would be an effective way of reducing diabetic burden in women and therefore reducing associated morbidity and mortality of T2DM globally [181, 182].

**233**

bidity [165].

vary by region.

**Acknowledgements**

HRB-MRCG-2016-2.

*The Role of Gender in the Onset, Development and Impact of Type 2 Diabetes Mellitus…*

With such a large proportion of society effected by DM and the fact that the major risk factors for T2DM comprise a generally unhealthy lifestyle, the lines between complications of the disease itself and disorders that are simply comorbid, but potentially highly important and relevant to the DM population, become blurred. For example, T2DM is a risk factor for vascular dementia, more so in women compared to men [183]. Women with T2DM also have increased depressive symptoms compared to men with T2DM and these symptoms correlate with worsening T2DM biological profiles [179]. Studying the role of gender in this wider range of comorbidities will be important for a greater understanding of the interplay between common modifiable risk factors and those non-communicable diseases that are increasing in prevalence worldwide. This will ultimately benefit

Gender also plays a role in response to and adherence to medication. While it has been demonstrated that there is no overall difference in medication adherence between women and men, Walker et al. demonstrated a significantly reduced adherence to Metformin in women and this was specifically related to women reporting worse adverse effects from the drug [179, 184]. Although advancements in therapies for DM include expensive pharmaceutical agents which are likely to increase the cost of treatment of DM per patient, significant reduction to overall spend may be achieved through effective reduction of complications [185]. Fewer complications and reduced severity of complications are not only beneficial for the overall costs of DM but also due to the obvious significant reduction in morbidity and mortality that would be associated. It is important that current and future medications are assessed for differential effects between women and men. A more recently explored treatment option, which has potential to rescue many of the disorders associated with T2DM is cell therapy. For many DM comorbidities, MSCs, for example, have been proposed as having a mechanistic role in both pathology and/or recovery [165, 186, 187]. There are fewer MSCs in the bone marrow of people with T2DM and considering the role of MSCs in repair and in reduction of inflammation, they are well poised as an effective treatment option [165]. Furthermore, there does not appear to be an impact of gender on the functioning of MSCs in tissue repair indicating they could benefit both women and men with T2DM comor-

In conclusion, there are important implications of gender in terms of the risk of DM itself and subsequently the disorders caused by and associated with it. These differences need to be taken into account in research into T2DM and its complications as well as in the treatment of those individuals diagnosed with the disease. The observed interplay between T2DM and gender warrants further epidemiological and molecular analyses in order to achieve a more complete understanding of the role of gender in the onset and prognosis of diabetic complications. This review also demonstrates that in terms of biomedical research it is of crucial importance for studies to include both genders in their research, and for gender to be recorded as a variable. This supports recommendations made by the SAGER (Sex and Gender Equity in Research) guidelines [188]. It will also be important to further study the mechanism by which gender exerts the described effects, which will be different for different comorbidities of DM, and will likely

Research Alliance under the MRCG-HRB Joint Funding Scheme, grant number

*DOI: http://dx.doi.org/10.5772/intechopen.94271*

the future wellbeing of those that live with DM.

#### *The Role of Gender in the Onset, Development and Impact of Type 2 Diabetes Mellitus… DOI: http://dx.doi.org/10.5772/intechopen.94271*

With such a large proportion of society effected by DM and the fact that the major risk factors for T2DM comprise a generally unhealthy lifestyle, the lines between complications of the disease itself and disorders that are simply comorbid, but potentially highly important and relevant to the DM population, become blurred. For example, T2DM is a risk factor for vascular dementia, more so in women compared to men [183]. Women with T2DM also have increased depressive symptoms compared to men with T2DM and these symptoms correlate with worsening T2DM biological profiles [179]. Studying the role of gender in this wider range of comorbidities will be important for a greater understanding of the interplay between common modifiable risk factors and those non-communicable diseases that are increasing in prevalence worldwide. This will ultimately benefit the future wellbeing of those that live with DM.

Gender also plays a role in response to and adherence to medication. While it has been demonstrated that there is no overall difference in medication adherence between women and men, Walker et al. demonstrated a significantly reduced adherence to Metformin in women and this was specifically related to women reporting worse adverse effects from the drug [179, 184]. Although advancements in therapies for DM include expensive pharmaceutical agents which are likely to increase the cost of treatment of DM per patient, significant reduction to overall spend may be achieved through effective reduction of complications [185]. Fewer complications and reduced severity of complications are not only beneficial for the overall costs of DM but also due to the obvious significant reduction in morbidity and mortality that would be associated. It is important that current and future medications are assessed for differential effects between women and men. A more recently explored treatment option, which has potential to rescue many of the disorders associated with T2DM is cell therapy. For many DM comorbidities, MSCs, for example, have been proposed as having a mechanistic role in both pathology and/or recovery [165, 186, 187]. There are fewer MSCs in the bone marrow of people with T2DM and considering the role of MSCs in repair and in reduction of inflammation, they are well poised as an effective treatment option [165]. Furthermore, there does not appear to be an impact of gender on the functioning of MSCs in tissue repair indicating they could benefit both women and men with T2DM comorbidity [165].

In conclusion, there are important implications of gender in terms of the risk of DM itself and subsequently the disorders caused by and associated with it. These differences need to be taken into account in research into T2DM and its complications as well as in the treatment of those individuals diagnosed with the disease. The observed interplay between T2DM and gender warrants further epidemiological and molecular analyses in order to achieve a more complete understanding of the role of gender in the onset and prognosis of diabetic complications. This review also demonstrates that in terms of biomedical research it is of crucial importance for studies to include both genders in their research, and for gender to be recorded as a variable. This supports recommendations made by the SAGER (Sex and Gender Equity in Research) guidelines [188]. It will also be important to further study the mechanism by which gender exerts the described effects, which will be different for different comorbidities of DM, and will likely vary by region.
